Opioid ligands act upon one or more of the four known opioid receptors, namely the μ (MOR), δ (DOR), κ (KOR) and opioid like (ORL) receptors. The opioid receptors belong to the class A (Rhodopsin-like) γ subfamily of G protein-coupled receptors (GPCRs) and have a common seven-transmembrane helical architecture. Of the four opioid receptors, the μ (MOR), δ (DOR) and κ (KOR) are more closely related, sharing approximately 70% sequence homology in their seven-transmembrane domains with more variation being present in their extracellular loops and even greater variation in their N and C termini. The crystal structure of the human KOR (hKOR) has been solved with the receptor in complex with the selective antagonist ligand JDTic, i.e. ((3R)-7-hydroxy-N-[(1 S)-1-(((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide. The hKOR binding pocket was found to be relatively large and partially capped by the extracellular loop 2 (ECL2) β-hairpin, with a relatively narrow and deep pocket containing an aspartate side chain (Asp138). The aspartate residue is conserved in all aminergic GPCRs, including the opioid receptors, and is critical in the selectivity of aminergic receptors towards protonated amine-containing ligands. Wu, H. et al. “Structure of the human kappa opioid receptor in complex with JDTic” Nature 2012 485(7398): 327-332.
Pharmacological studies have reported that the KOR is a GVo-coupled receptor which is selectively activated by endogenous dynorphin opioid peptides. The KOR has been found to be widely expressed in the brain, spinal cord and peripheral tissues. Particular areas of the brain in which the KOR is found have been associated with reward, cognitive function and stress responsiveness and include the ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex, hippocampus, striatum, amygdala, locus coeruleus, substantia nigra, dorsal raphe nucleus and hypothalamus. Evidence has shown that dynorphin levels are increased under painful and stressful conditions and that disruption of the KOR can produce an anti-stress effect. Stress and drugs of abuse have been found to cross-modulate dynorphin-dependent molecular pathways, indicating that stress-induced dynorphin release and KOR activation are involved in pharmacological processes related to depression and substance abuse. Findings such as these have stimulated interest in seeking KOR antagonists as potential pharmacotherapies for disorders such as depression, anxiety, addictive disorders or other stress associated psychiatric conditions. For example, KOR antagonist compounds may be useful in the treatment of addiction, such as relapse addiction, to drug substances such as the psychostimulants cocaine, amphetamine, methamphetamine and the like; opioids such as heroin, morphine, oxycodone, hydrocodone, hydromorphone and the like; nicotine; cannabinoids, such as marijuana; and alcohol. In addition, KOR antagonists may also be useful for treatment of depression and other psychiatric disorders. (See e.g. Bruchas, M. R. et al. “The Dynorphin-Kappa Opioid System as a Modulator of Stress-induced and Pro-addictive Behaviors”, Brain Res. 2010 Feb. 16; 1314C:44;doi:10:1016/j.brainres.2009.08.062; Lalanne, L. et al. “The kappa opioid receptor: from addiction to depression, and back”, Frontiers in Psychiatry 2014, 5, 170; doi: 10.3389/fpsyt.2014.00170; and Kissler, J. L. et al. “The One-Two Punch of Alcoholism: Role of Central Amygdala Dynorphins/Kappa-Opioid Receptors” Biol. Psychiatry 2014, 75, 774-782; doi: 10.1016/j.biopsych. 2013.03.014.)
New or improved agents that modulate (such as antagonize) kappa opioid receptors are needed to provide improved therapeutic options for the treatment of diseases or conditions associated with dysregulated activity of the kappa opioid receptor/dynorphin system, such as those described herein. It may also be desirable to devise new agents which exhibit selectivity for the kappa opioid receptor over the closely related mu and delta opioid receptors. See e.g. Urbano, M. et al. “Antagonists of the kappa opioid receptor”, Bioorganic & Medicinal Chemistry Letters 2014, 24, 2021-2032; Munro, T. A. et al. “Selective K Opioid Antagonists nor-BNI, GNTI and JDTic Have Low Affinities for Non-Opioid Receptors and Transporters”, Plos One 2013, 8(8) e70701; doi:10.1371/journal.pone.0070701; Mitch, C. H. et al. “Discovery of Aminobenzyloxyarylamides as K Opioid Receptor Selective Antagonists: Application to Preclinical Development of a K Opioid Receptor Antagonist Receptor Occupancy Tracer”, J. Med. Chem. 2011, 54, 8000-8012; doi: 10.1021/jm2007789r; and Rorick-Kehn, L. M. et al. “Determining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 Using Pupillometry as a Translational Biomarker in Rat and Human”, International Journal of Neuropsychopharmacology 2015, 1-11; doi: 10.1093/ijnp/pyu036.